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Bipolar Androgen Therapy in Metastatic Castrate Resistant Prostate Cancer With Homologous Recombination Deficiency (HiTeCH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03522064
Recruitment Status : Recruiting
First Posted : May 11, 2018
Last Update Posted : September 18, 2019
Sponsor:
Information provided by (Responsible Party):
Anthony Joshua, FRACP, St Vincent's Hospital, Sydney

Brief Summary:
The purpose of this study is to determine the efficacy of BAT in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD). Bipolar androgen therapy will be administered to men confirmed to have HRD on tumour tissue and/or circulating tumour DNA analysis on pre-screening.

Condition or disease Intervention/treatment Phase
Castration-resistant Prostate Cancer Homologous Recombination Deficiency Drug: Testosterone Enanthate Phase 2

Detailed Description:

Androgen deprivation therapy (ADT) remains the mainstay of prostate cancer treatment. Though an effective therapy initially, the side effects of ADT are numerous and treatment resistance is inevitable. Castrate-refractory prostate cancer (CRPC) progresses via adaptive mechanisms that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens.

The concept of cycling between supra- and sub physiological levels of testosterone has been tested recently in studies of "bipolar androgen therapy" (BAT) in which patients are given high dose testosterone in combination with androgen deprivation therapy (ADT) via an LHRH agonist/antagonist. Studies of BAT using IM testosterone have been promising both in terms of PSA responses and quality of life improvements. Additionally, these early phase studies suggest the potential for re-sensitisation to novel anti-androgen therapies.

Though responses have been positive in these early studies a proportion of men fail to respond and data to guide patient selection is lacking. There are data to suggest that patients with DNA repair deficits may be particularly responsive to BAT. Whether these changes serve as predictors of response is unknown as the effect of BAT on the tumour, its microenvironment and peripheral circulating tumour DNA has not been studied in detail. Information on treatment effects may be key to appropriate patient selection for this treatment.

The aim of this study is to assess homologous repair deficiency as a predictive biomarker of response to bipolar androgen therapy in men with metastatic castrate-refractory prostate cancer and to study the effects of this treatment on ctDNA and intra-tumoural gene expression.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Dose Testosterone in Men With Advanced Prostate Cancer and Homologous Recombination Deficiency
Actual Study Start Date : July 30, 2018
Estimated Primary Completion Date : July 30, 2021
Estimated Study Completion Date : July 30, 2021


Arm Intervention/treatment
Experimental: High dose testosterone
500mg IM enanthate every 4 weeks in combination with ongoing LHRH agent (unless post-orchidectomy).
Drug: Testosterone Enanthate
Testosterone Enanthate is the oil-soluble ester of the androgenic hormone testosterone. Testosterone Enanthate is a clear to pale yellow solution for intramuscular injection. Each pre-filled syringe contains 250mg testosterone enanthate/1mL.
Other Name: Primoteston Depot




Primary Outcome Measures :
  1. PSA Response Rate [ Time Frame: 1 year ]
    >/= 50% fall from baseline PSA


Secondary Outcome Measures :
  1. Time to PSA progression [ Time Frame: 1 year ]
    Time to increase in PSA >/=25% from baseline or nadir confirmed on subsequent test >1 week later

  2. Quality of Life [ Time Frame: 1 year ]
    FACT-P

  3. Radiological Response Rate [ Time Frame: 1 year ]
    RECIST or PCWG3 Criteria

  4. Safety and Tolerability (Frequency of adverse events as assessed by NCI CTCAE v4.0) [ Time Frame: 1 year ]
    Frequency of adverse events as assessed by NCI CTCAE v4.0


Other Outcome Measures:
  1. Changes in ctDNA expression from baseline [ Time Frame: 1 year ]
    Exploratory

  2. Change in serum testosterone and oestradiol levels [ Time Frame: 1 year ]
    Change in serum levels from baseline to Days 14 and 28 of cycle 1



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males with histologically confirmed adenocarcinoma of the prostate
  2. Confirmed HRD (Homologous recombination defect) in germline and/or somatic DNA analysis (tumour or blood), by a validated assay (see Appendix 1). Mutations in HR genes not listed in appendix 1 will be considered in literature suggests pathogenicity. A maximum of 10 uncharacterised or heterozygous mutations will be included.
  3. Age ≥ 18 years
  4. ECOG performance status ≤ 1
  5. Rising PSA confirmed on two sequential tests ≥1 week apart and a minimum value of 2 ug/L despite castrate levels of testosterone
  6. Serum testosterone < 1.7 nmol/L and on an LHRH agent or post orchidectomy ≥ 1 year.
  7. Washout of ≥ 4 weeks from prior line of treatment, radiotherapy or surgery (aside from LHRH agent)
  8. Adequate bone marrow function (platelets > 100 x 109/L, ANC > 1.5 x 109/L, Hb >100)
  9. Adequate liver function (ALT/AST < 1.5 x ULN, bilirubin < 2 x ULN)
  10. Adequate renal function (creatinine clearance > 50 ml/min)
  11. Adequate cardiac function and reserve after cardiology assessment
  12. Archived tissue sample available or willingness to undergo fresh biopsy
  13. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
  14. Signed, written informed consent

Exclusion Criteria:

  1. Contraindications to investigational product
  2. Pain due to metastatic prostate cancer requiring opioid analgesics
  3. Evidence of disease progression in sites or extent that, in the opinion of the investigator, would put the patient at risk from testosterone therapy and its potential for initial tumour flare (eg: femoral metastasis at risk of fracture, ureteric obstruction due to nodal disease or cord compression due to spinal metastases).
  4. Previous treatment with platinum chemotherapy and/or a PARP inhibitor. However up to 8 men with prior treatment to these agents will be included as an exploratory cohort.
  5. Life expectancy of less than 3 months.
  6. Brain metastases or leptomeningeal disease
  7. History of thromboembolic event and not currently on anticoagulation
  8. Prior myocardial infarction or unstable angina within 2 years of study entry
  9. Haematocrit ≥ 50%, untreated severe obstructive sleep apnoea or poorly controlled heart failure (NYHA >1)
  10. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
  11. Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
  12. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03522064


Contacts
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Contact: Robert Kent +61293555611 SVHS.CancerResearch@svha.org.au

Locations
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Australia, New South Wales
Kinghorn Cancer Centre, St. Vincent's Hospital Recruiting
Sydney, New South Wales, Australia, 2010
Contact: Robert Kent    0293555611    SVHS.CancerResearch@svha.org.au   
Sponsors and Collaborators
St Vincent's Hospital, Sydney
Investigators
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Principal Investigator: Anthony M Joshua, MBBS, PhD, FRACP St. Vincent's Hospital-Manhattan

Publications:
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Responsible Party: Anthony Joshua, FRACP, Principal Investigator, St Vincent's Hospital, Sydney
ClinicalTrials.gov Identifier: NCT03522064    
Other Study ID Numbers: HiTECH
First Posted: May 11, 2018    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Anthony Joshua, FRACP, St Vincent's Hospital, Sydney:
Castrate-resistant prostate cancer
bipolar androgen therapy
homologous recombination deficiency
BRCA
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Methyltestosterone
Testosterone
Testosterone undecanoate
Testosterone enanthate
Testosterone 17 beta-cypionate
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents